A systematic review of the safety and efficacy of currently used treatment modalities in the treatment of patients with PIK3CA-related overgrowth spectrum

Sarah M Bernhard; Luise Adam; Hady Atef; Dario Häberli; Wichor M Bramer; Beatrice Minder; Yvonne Döring; Jessica E Laine; Taulant Muka; Jochen Rössler; Iris Baumgartner

doi:10.1016/j.jvsv.2021.07.008

A systematic review of the safety and efficacy of currently used treatment modalities in the treatment of patients with PIK3CA-related overgrowth spectrum

J Vasc Surg Venous Lymphat Disord. 2022 Mar;10(2):527-538.e2. doi: 10.1016/j.jvsv.2021.07.008. Epub 2021 Aug 3.

Authors

Affiliations

¹ Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
² Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Institute of Primary Health Care, University of Bern, Bern, Switzerland.
³ Faculty of Physical therapy, Cairo University, Cairo, Egypt; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
⁴ Medical Library, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁵ Public Health and Primary Care Library, University Library of Bern, University of Bern, Bern, Switzerland.
⁶ Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany.
⁷ Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
⁸ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
⁹ Division of Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁰ Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. Electronic address: iris.baumgartner@insel.ch.

PMID: 34358672
DOI: 10.1016/j.jvsv.2021.07.008

Abstract

Background: PIK3CA (activating mutations of the p110α subunit of phosphatidylinositol 3-kinases)-related overgrowth spectrums (PROS) include a variety of clinical presentations that are associated with hypertrophy of different parts of the body. We performed a systematic literature review to assess the current treatment options and their efficacy and safety for PROS.

Methods: A literature search was performed in Embase, MEDLINE (Ovid), Web of Science Core Collection, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Google Scholar to retrieve studies on the treatment of hypertrophy in PROS. Randomized controlled trials, cohort studies, and case series with ≥10 patients were included in the present review. The titles, abstracts, and full text were assessed by two reviewers independently. The risk of bias was assessed using the Newcastle-Ottawa scale.

Results: We included 16 studies of the treatment of hypertrophy in PROS patients, 13 (81.3%) from clinical retrospective studies and 3 (13.7%) from prospective cohort studies. The risk of bias grade was low for 2, medium for 12, and high for 2 studies. Of the 16 studies, 13 reported on surgical treatment and 3 reported pharmacologic treatment using phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway inhibitors in PROS patients. In 3 studies, PROS was defined by a mutation in the PIK3CA gene, and 13 studies relied on a clinical definition of PROS. Surgical therapy was beneficial for a specific subgroup of PROS (macrodactyly). However, little has been reported concerning surgery and the potential benefits for other PROS entities. The reported side effects after surgical therapy were mostly prolonged wound healing or scarring. PI3K/mTOR pathway inhibition was beneficial in patients with PROS by reducing hypertrophy and systemic symptoms. The adverse effects reported included infection, changes in blood count, liver enzymes, and metabolic measures.

Conclusions: Surgery is a locally limited treatment option for specific types of PROS. A promising treatment option for PROS is pharmacologic PIK3CA inhibition. However, the level of evidence on the treatment of overgrowth in PROS patients is limited.

Keywords: Phosphatidylinositol 3-kinase; Phosphoinositide-3 kinase inhibitors; TOR serine-threonine kinases.

Publication types

Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
Class I Phosphatidylinositol 3-Kinases / genetics
Class I Phosphatidylinositol 3-Kinases / metabolism
Genetic Predisposition to Disease
Humans
Hypertrophy / diagnosis
Hypertrophy / enzymology
Hypertrophy / genetics
Hypertrophy / therapy*
MTOR Inhibitors / adverse effects
MTOR Inhibitors / therapeutic use*
Molecular Targeted Therapy
Mutation
Phenotype
Phosphoinositide-3 Kinase Inhibitors / adverse effects
Phosphoinositide-3 Kinase Inhibitors / therapeutic use*
Signal Transduction
Surgical Procedures, Operative* / adverse effects
Syndrome
Treatment Outcome

Substances

MTOR Inhibitors
Phosphoinositide-3 Kinase Inhibitors
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human